The objective of this proposal is to study the cellular mechanisms of action of cannabinoid ligands in the brain. Cannabinoid substances have powerful psychoactive properties and alter many physiological processes such as learning and memory. Cannabinoids effects in brain are mediated via specific receptors (CB1), and it has now become clear that marijuana interacts with a naturally occuring physiological system of endogenous transmitters, the endocannabinoids. Our studies will be performed in a structure involved in learning and memory processes, the hippocampus, which exhibits one of the highest densities of CB1 receptors. We will combine state-of-the-art electrophysiological techniques to assess the cannabinoid modulation of synaptic transmission and potentiation, as well as conductances that govern neuronal excitability. This proposal will be focused on the role played by the endocannabinoids and their interaction with 9-tetrahydrocannabinol (THC), the active substance contained in marijuana. The physiological effects of natural cannabinoids will be explored in mature CA1 pyramidal neurons and interneurons using the hippocampal slice preparation. The rationale for this proposal centers on the hypothesis that THC alters normal brain function by interfering with a system of natural ligands. THC and the endocannabinoids are partial agonists at CB1, and moderately affect neuronal activity when compared to full (synthetic) CB1 agonists. Yet, most studies to date have been performed with synthetic agonists. In this proposal, emphasis will be placed on the role and mechanisms of action of natural cannabinoids. The specific aims are to: 1) establish a role for endogenous cannabinoids in long-term potentiation; 2) examine cannabinoid effects on neurotransmission; 3) assess the modulation of interneuron activity by cannabinoids; 4) investigate the mechanisms of M- current regulation by cannabinoids. This approach will allow us to determine more precisely the influence of THC and its interaction with the naturally occuring cannabinoid modulatory system in the central nervous system. The goal of the proposed research is to understand the physiological role of the naturally occuring cannabinoid system. The evaluation of the neurobiological substrates and their interaction with substances of exogenous origin promise to yield new understanding of the physiological phenomenon associated with the consumption of marijuana, and have implications for the etiology and treatment of drug abuse.